Tumors characteristically express atypical, potentially immunoreactive antigens that are collectively referred to as tumor antigens. Accumulating evidence suggests that the failure of the immune system to mount an effective response against progressively growing tumors is not attributable to a lack of recognizable tumor antigens. Immunosuppression by tumors is poorly understood and mechanisms by which tumors may escape immune surveillance have been poorly explored. Recently, it has been shown that cytotoxic T cells become tolerized by a reduction in local concentrations of tryptophan that are elicited by indoleamine 2,3-dioxygenase (IDO; EC 1.13.11.42) activity. Furthermore, IDO has been implicated in tumor immunosuppression (Muller et al. (2005) Nat. Med., 11:312-9; Munn et al. (2004) Trends Mol. Med., 10:15-18; Uyttenhove et al. (2003) Nat. Med., 9:1269-74; Friberg et al. (2002) Intl. J. Cancer, 101:151-155).
Dietary catabolism of tryptophan is mediated by the structurally unrelated liver enzyme tryptophan dioxygenase (TDO2; 1.13.11.11). IDO is an extrahepatic oxidoreductase that catalyzes the initial and rate-limiting step in the degradation of tryptophan along the kynurenine pathway that leads to the biosynthesis of nicotinamide adenine dinucleotide (NAD+) (Sono et al. (1996) Chem. Rev., 96:2841-87; Botting et al. (1995) Chem. Soc. Rev., 24:401-12; Sono et al. (1980) Biochem. Rev., 50:173-81). IDO is a monomeric 45 kDa heme-containing oxidase that is active with the heme iron in the ferrous (Fe+2) form. The ferric (Fe+3) form of IDO is inactive and substrate inhibition is believed to result from tryptophan (Trp) binding to ferric IDO (Sono et al. (1980) J. Biol. Chem., 255:1339-45; Kobayashi et al. (1989) J. Biol. Chem., 264:15280-3). The primary catalytic cycle of IDO does not involve redox changes, nevertheless IDO is prone to autooxidation and therefore a reductant is necessary to reactivate the enzyme. In vivo, IDO purportedly relies on a flavin or tetrahydrobiopterin co-factor. In vitro, methylene blue and ascorbic acid are believed to substitute for the natural flavin or tetrahydrobiopterin co-factor.
Inhibition of IDO has previously been targeted for other therapies, most notably neurological disorders (Botting et al. (1995) Chem. Soc. Rev., 24:401-12). Several metabolites of the kynurenine pathway are neurotoxic or are implicated in neurodegeneration, e.g. quinolinic acid, and therefore attention has focused on IDO. A recent review summarizes the range of compounds that have been tested as IDO inhibitors (Muller et al. (2005) Expert. Opin. Ther. Targets., 9:831-49).